IL115891A - Hemorrhoidal compositions and their use - Google Patents
Hemorrhoidal compositions and their useInfo
- Publication number
- IL115891A IL115891A IL11589195A IL11589195A IL115891A IL 115891 A IL115891 A IL 115891A IL 11589195 A IL11589195 A IL 11589195A IL 11589195 A IL11589195 A IL 11589195A IL 115891 A IL115891 A IL 115891A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
An aqueous gel composition for intrarectal administration in the treatment of hemorrhoids and/or in the treatment of anorectal disease which contains one or more drugs effective in such treatment and a carrier comprising a water soluble cellulose derivative as gelling agent in an amount from about 0.2% to about 10% by weight of the total composition, propylene glycol as humectant in an amount of from about 5% to about 45% by weight of the total composition and water in an amount up to about 94% by weight of the total compositio
Description
Hemorrhoidal compositions and their use WHITEHALL LABORATORIES LIMITED C. 99813 -I- 115891.3 This invention relates to uses of gel compositions for the treatment of hemorrhoids and/or diseases of the anorectum. More particularly 115891/2 teaches the addition of sucralfate to hemorrhoidal compositions and illustrates a gel formulation based on Samuet. No humectant or lubricant is present. EP Publication No 225832 describes a composition in gel form containing a silica gelling agent and a vegetable oil of natural origin which has been hyperoxygenated. US Patent No 4518583 teaches a composition which can be in gel form for use in treating hemorrhoids and anorectal diseases comprising a peroxide and containing glycerine as humectant, emollient and lubricant.
GB 1261881 teaches pharmaceutical compositions which are in the form of gels containing witch hazel astringent. The compositions are described as particularly useful for bruises, sprains, insect bites and skin irritations. No mention is made of treating hemorrhoids. As gelling agent GB 1261881 teaches the use of carboxy vinyl co-polymer. The Applicants have found carboxy vinyl co-polymer produced a gel which was unsuitable for hemorrhoidal use because of the watery non-lubricating nature of the gel.' European Patent No 386960 describes a wound dressing composition which is a semi-viscous pourable liquid at room temperature but which sets to form a rigid gel or flexible film in contact with the human body. The composition contains as an essential ingredient a compound having reversible thermosetting gel properties illustrated by Pluronic F-127 in amounts from 1 to 30%. The resulting rigid gels do not possess the lubricating and water retaining properties provided by the gels of the present invention.
Currendy marketed topical hemorrhoidal compositions are either ointments or suppositories for application directly to the affected part or region of the body. Such compositions are generally based on a carrier comprising one or more fatty, oily or greasy components which are used to impart lubricating properties to the composition and thereby facilitate the administration of the composition by the user. The aim of such treatment is to provide the user with varying degrees of symptomatic relief in particular before and during defecation.
One of the main disadvantages of compositions based on fatty, greasy or oily components as carriers is the staining or soiling of clothing which can accompany their use. Aqueous compositions on the other hand are easier to remove from clothing.
Additionally where greasy compositions are applied to affected parts by hand, users can experience added difficulties in washing their hands scrupulously clean. Yet a further disadvantage is that hydrophilic drugs are insoluble or of low solubility in fatty, oily or greasy carriers and therefore drug absorption from such compositions may be poor.
While there is a need for a hemorrhoidal carrier with satisfactory lubricant properties while possessing reduced stain or soiling properties and providing improved drug bioavailability.
It has surprisingly been found that a gel based on a water soluble cellulose derivative as gelling agent, propylene glycol as humectant and water in defined ranges possesses excellent lubricating properties and water-retaining properties such as to provide effective symptomatic relief for hemorrhoid sufferers. Such an aqueous gel base is also particularly compatible with ionic active ingredients. Further advantages of said gel base are that it avoids oily, greasy and fatty components, it is water miscible, and it is clear thereby avoiding staining or soiling of clothing. It can also be easily washed from the users hands. The combination of gelling agent and humectant also provides excellent water retaining properties after applying to the anus thereby giving a long term -4- agents are hydroxy ethylcellulose, hydroxypropylmethy .cellulose, methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose and carboxymethylcellulose and combinations thereof. The preferred gelling agent is hydroxyethylcellulose.
Also preferred are compositions comprising propylene glycol in an amount from about 10 to about 30% by weight, preferably about 12 to about 18% by weight, most preferably about 15% by weight.
The water present in the formulation advantageously provides a cooling effect in use and can be adjusted relative to the amounts of the other ingredients especially the gelling agent to give a satisfactory viscosity to the ge.L It is preferred that the viscosity is high enough so that the gel is not too mobile and so is retained in the anus when applied thereto, yet low enough so that the gel can be dispensed satisfactorily from a tube or other dispenser. A further advantage of a water based gel is that dispensers may be cold-filled unlike grease based ointments which are generally hot filled to achieve a lower viscosity so that the tubes may be filled prior to cooling.
To achieve the desired water content, the water may be incorporated by adding some or all in the form of hamamelis water. Hamamelis water is a clear colorless liquid with astringent properties. Astringents are effective when applied to the skin or mucous membranes for a local and limited effect. Astringents coagulate the protein in the skin cells, thereby protecting the underlying tissue and decreasing the cell volume. When appropriately used, astringents lessen mucous and other secretions and help relieve local anorectal irritation and inflammation.
Hamamelis water in a concentration of 10-50% is recommended as an astringent for external use in anorectal disorders. Hamamelis water is prepared by macerating recently cut and partially dried dormant twigs of Hamamelis virginiana L in water, distilling and adding the requisite quantity of ethanol to the distillate, e.g. about 13 to 15% v/v. Typical quantities of hamamelis water used in the compositions of this invention comprise from about 10 to about 60% by weight of the total composition, e.g. 35-55%, preferably about 50% by weight . Additional water may be added to adjust the viscosity to that desired. Accordingly hamamelis water functions both as a source of one or the active ingredient for the composition (i.e. an astringent) and also for providing some or all of the water content. Ethanol is present in the hamamelis water and may therefore be another constituent of the formulations of this invention. The presence of -5- ethanol also enhances the solubility of the active constituents and may comprise 0 to about 10% by weight of the total composition.
Other ingredients and active constituents may be incorporated in the gel composition of this invention especially other astringents, vasoconstrictors, topical steroidal anti-inflammatories, such as hydrocortisone or prednisolone, and/or local anaesthetics to provide symptomatic relief and/or ameliorate the pain accompanying defecation. Preferably such active ingredients are water soluble (e.g. ionic) in which case the carrier base allows a faster onset of action because the actives are held in solution. The viscous properties of the gel also minimise physical risk of loss due to run out.
Examples of astringents that may be used are zinc oxide and calamine. However hamamelis water is particularly preferred as astringent since being a solution it is particularly suited to, and mutually compatible with, the hydrophilic carrier base of this invention. It is especially preferred that the ingredients and active constituents are colourless and for this reason hamamelis water is also particularly preferred since it provides a clear formulation. Crystal clear formulations which are provided by this invention are also very much preferred because the clarity of the gel is perceived by the user as depicting cleanliness thereby optimising user confidence and user compliance.
Examples of vasoconstrictors that can be used are phenylephrine hydrochloride, ephedrine sulphate, epinephrine and epinephrine hydrochloride. The preferred vasoconstrictor is phenylephrine hydrochloride in an amount up to about 0.35 % w/w of the total composition, e.g. about 0.1 to about 0.3%, preferably about 0.25%.
Phenylephrine HCl is believed to relieve itching caused by histamine release and reduces congestion in the anorectal area. It acts primarily on the alpha-adrenergic receptors and produces vasoconstriction by a direct effect on receptors rather than by norephinephrine displacement. Recommended dosage is 0.25% applied up to 4 times a day. When phenylephrine is used we have found it particularly advantageous for stability to incorporate an antioxidant system in the formulation.
Local anaesthetics that can be incorporated as active ingredients in the compositions of this invention include benzocaine (e.g. 5 to 20% by weight) benzyl alcohol (e.g. 1 to 4% by weight); dibucaine (HCl) (e.g. 0.25 to 1% by weight); lidocaine -6- e.g. (0.5 to 5% by weight); pramoxine hydrochloride (e.g. about 1% by weight) and tetracaine (HC1) e.g. 0.5 to 1% by weight).
In a further aspect this invention provides a composition for treating hemorrhoids consisting essentially of hamamelis water up to about 50% by weight of total composition; propylene glycol from about 10 to about 20% by weight of composition; hydroxethylcellulose from about 1 to about 2.5% by weight, and water qs 100 per cent by weight. Phenylephrine hydrochloride may also be present in an amount from about 0.2 to 0.3% by weight.
: The composition of the invention may also comprise further excipients including antioxidants and preservatives as required. When phenylephrine HC1 is used as an active ingredient preferred antioxidants are sodium citrate (0.3 to 20%), sodium metabisulphite(0.01 - 1%) and disodium edetate (0.005 to 0.1%) where the figures in brackets show the preferred concentrations. Preservatives that can be used include methyl and/or propyl p-hydroxybenzoate.
In an especially preferred aspect this invention provides a topical hemorrhoidal composition as herein described in the form of an aqueous clear gel incorporating one or more soluble actives.
The compositions of this invention may be prepared by mixing the ingredients in any convenient order and allowing a gel to form. In a preferred sequence, the compositions of this invention may be prepared by dispersing the water soluble cellulose derivative in a portion e.g about 2/3 of the propylene glycol and adding to the water constituents comprising hamamelis water if required and any further active drug component and the remainder of the propylene glycol. The resulting mixture is stirred until a gel is formed, e.g for up to 1 hour. -7- EXAMPLE 1 Gel compositions of the present invention based on hamamelis water and phenylephrine hydrochloride as actives are prepared by the following general procedure: Any salts to be incorporated (phenylephrine hydrochloride, sodium citrate, sodium metabisulphite, disodium edetate) are dissolved in hamamelis water and deionised water to give a clear solution. Methyl and propyl p-hydroxybenzoates are dissolved in approximately one third of the amount of propylene glycol to be used and added to the salt solution.; The water soluble cellulose derivative (hydroxyethylcellulose) - -is dispersed in the remaining (approximately two thirds) propylene glycol and added to the salt/p-hydroxybenzoate solution. The resulting mixture is stirred and homogenised in a jacketed Giusti vessel until a clear homogenous gel is formed. No heating is necessary during the manufacture and therefore all steps can be carried out at ambient temperature.
The following clear gel formulations are prepared according to the above procedure: INGREDIENT FORMULATION NO 1 2 3 4 5 %w/w %w/w %w/w %w/w %w/w Hydroxyethylcellulose 1.75 2.00 2.25 1.50 2.0 Propylene glycol 15 15 20 12 12 Phenylephrine HC1 - 0.25 0.25 0.25 - Sodium citrate - 0.30 0.30 0.30 - Sodium metabisulphite - 0.50 0.50 0.50 - Disodium edetate - 0.10 0.10 0.10 - Methyl p-hydroxybenzoate 0.20 0.20 0.20 0.20 0.20 Propyl p-hydroxybenzoate 0.05 0.05 0.05 0.05 0.05 Hamamelis water 50 50 50 50 50 Deionised water 33.0 31.60 26.35 35.10 35.75 100% 100% 100% 100% 100% b) In the case of Formulation No 2 the amounts shown below were used to produce a 50 kg batch. -8- Natrosol (250 HHX-Pharm) 1.000 kg Propylene glycol 7.500 kg Phenylephrine HC1 0.125 kg Sodium citrate 0.150 kg Sodium metabisulphite 0.250 kg Disodium edetate 0.050 kg Methyl p-hydroxybenzoate 0.100 kg Propyl p-hydroxybenzoate 0.025 kg Distilled witch hazel 25.000 kg Deionised distilled water 15.800 kg 50.000 kg The manufacturing process was as follows: 1. It was ensured that the working area and equipment were clean. A 50 litre Giusti Pharmix mixer (J.l 1544B) vessel was wiped down inside with clean cloth impregnated with 70% ethanol solution. 2. 25.0 kg Distilled witch hazel (hamamelis water) and 15.8 kg deionised water were placed into the Giusti vessel. The initial temperature was recorded. 3. 0.125 kg Phenylephrine HC1, 0.150 kg sodium citrate, 0.05 kg disodium edetate, 0.25 kg sodium metabisulphite were added into the Giusti vessel and stirred with contra-rotating stirrers and emulsifier. Stirring time: 25 minutes. Contra-rotating stirrer speed: Inner at 14 rpm ; Outer at 30 rpm. Emulsifier speed: Slow (1400 rpm). 4. Into a separate stainless steel vessel 0.10 kg methyl p-hydroxybenzoate and 0.025 kg propyl p-hydroxybenzoate were added to 2.5 kg propylene glycol using a propeller stirrer (D a-Labortechnik RW20DZM) (at 250 rpm) fitted with a 10 cm squared paddle until dissolved. Stirring speed: 250 rpm. Stirring time 20 minutes. 5. The solution from step 4 was added to the Giusti vessel and stirred with the contra-rotating stirrer and emulsifier. Stirring time: 20 minutes. Contra-rotating stirrer speed: Inner at 14 rpm; Outer at 30 rpm. Emulsifier speed: Slow (1400 rpm). -9- 6. To the same stainless steel vessel from step 4, 5.0 kg propylene glycol was added and while stirring with propeller stirrer, 1 kg hydroxyethyl cellulose (Natrosol 250 HHX-Pharm., as supplied by Aqualon Ltd) was added slowly until fully dispersed. Stirring time: 20 minutes. Stirring speed: 250 rpm 7. The dispersion from step 5 was poured very slowly into the Giusti Vessel and stirred with contra-rotating stirrer and emulsifier. 8. The product was stirred under vacuum using the outer stirrer only to de-aerate the product. The final temperature was recorded. Stirring time: 30 minutes. Outer stirrer speed: 30 rpm. Pressure: -1 bar. 9. The product was transferred to a stainless steel vessel prior to packaging in 25 g and 50 g tubes.
The formulations had the following physical properties: pH : 6.07 Viscosity : 43,500 cps Density : 1.014g/cm3 Appearance : Clear gel -10- EXAMPLE 2 Gel formulations 6 and 7 below (laboratory scale) were prepared based on the following: Gelling system: Natrosol (250 HHX-Pharm) (hydroxyethylcellulose) Anti-oxidant/Chelating system: Sodium citrate Sodium metabisulphite Disodium edetate Preservative system: Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Actives: Hamamelis water (distilled witch hazel) and phenylephrine HC1. a) Formulation 6 The % amounts used were as follows: Formulation 6 Materials % w/w A Natrosol (hydroxyethylcellulose) 1.75 Propylene glycol 10.00 B Phenylephrine HC1 0.25 Na citrate 0.30 Na metabisulphite 0.50 Disodium edetate 0.10 C Methyl p-hydroxybenzoate 0.20 Propyl p-hydroxybenzoate 0.05 Propylene glycol 5.00 D Distilled witch hazel 50.00 DI distilled water to 100.00 The method used was as set out in Example 1, i.e: - Dissolve B in D. Set aside - Dissolve methyl and propyl p-hydroxybenzoates in one third of the propylene glycol until dissolved (stirring approximately 30 mins.) - Add C to B + D - Predisperse Natrosol in propylene glycol. Add to (B+D+C) solution.
- Leave stirring till a clear gel is formed (approximately 1 hour) -11- b) Formulation 7 A similar formulation was prepared using the following amounts: Formulation 7 Material Amount (g) Natrosol (hydroxyethylcellulose) 17.49 g Propylene glycol 150.00 g Methyl p-hydroxybenzoate 2.00 g Propyl p-hydroxybenzoate 0.51 g Phenylephrine HC1 17.49 g Sodium citrate 3.00 g Disodium edetate 1.00 g Sodium metabisulphite 5.00 g Hamamelis water 500.00 g Distilled water 318.51 g In both cases gels were obtained with the following physical properties: pH Viscosity (cps) Colour @ 10 rpm/S96 Formulation 6 5.50 66,000 Transparent Formulation 7 6.05 48,000 Transparent Viscosity was measured using a Brookfield Viscometer Model DVII+ using an S96 spindle and a spin rate of 10 revolutions per minute at 20 °C.
Viscosity and pH values were acceptable for a topical gel formulation. -12- EXAMPLE 3 In a similar manner to Example 2a) gel formulations of this invention were prepared containing a steroidal anti-inflammatory agent with the following amounts of ingredients: Ingredient (Approved Name) Quantity (%w/w) Quantity (g) Hydroxyethylcellulose Ph Eur 2.00 10.00 Propylene glycol Ph Eur 30.00 150.00 Sodium citrate Ph Eur 0.60 3.00 Sodium metabisulphite Ph Eur 0.15 0.75 EDTA Disodium salt Ph Eur 0.10 0.50 Methyl hydroxybenzoate Ph Eur 0.20 1.00 Propyl hydroxybenzoate Ph Eur 0.05 0.25 Phenylephrine HC1 0.25 1.25 Prednisolone 0.05 0.25 Lidocaine Hydrochloride 3.00 15.00 Cetrimide 0.13 0.63 Deionised Water 63.47 317.37 TOTAL 100.00 500.00 Ingredient (Approved Name) Quantity (% /w) Quantity (g) Hydroxyethylcellulose Ph Eur 2.00 10.00 Propylene glycol Ph Eur 15.00 75.00 Sodium citrate Ph Eur 0.60 3.00 Sodium metabisulphite Ph Eur 0.15 0.75 EDTA Disodium salt Ph Eur 0.10 0.50 Methyl hydroxybenzoate Ph Eur 0.20 1.00 Propyl hydroxybenzoate Ph Eur 0.05 0.25 Phenylephrine HC1 0.25 1.25 Hydrocortisone 0.50 2.50 Lidocaine Hydrochloride 3.00 15.00 Cetrimide 0.13 0.63 Deionised Water 78.02 390.12 TOTAL 100.00 500.00 -13- EXAMPLE 4 This example illustrates the large scale (50 kg) preparation of a clear topical gel formulation of this invention.
The manufacturing method used is summarised below: Step 1 Distilled Witch Hazel and distilled water were placed into a 75 litre Giusti vessel.
Step 2 Phenylephrine HC1, sodium citrate, EDTA, sodium metabisulphite were added to the Giusti vessel and stirred @ 30 rpm and emulsified . @ slow speed (1400 rpm) for 25 minutes.
Step 3 Methyl and propyl p-hydroxybenzoates were dissolved in 1/3 of the total propylene glycol using a separate steel vessel and agitator (Ika- Labortechnik RW20DZM) with squared paddle for 30 minutes.
Step 4 Solution from Step 3 was added to Giusti vessel and stirred @ 25 rpm and emulsified @ slow speed 1400 rpm for 20 minutes.
Step 5 In same steel vessel as used above Natrosol was dispersed in the remainder of the propylene glycol (2/3 of the total content) using the previous agitator and paddle for 20 minutes.
Step 6 Dispersion from Step 5 was poured slowly in to the Giusti Vessel and stirred @ 30 rpm and emulsified @ slow speed 1400 rpm for 30 minutes. The product was de-aerated at 1 bar negative pressure. - ■14- The following quantities were used: Natrosol (250 HHX-Pharm) 0.875 k g Propylene glycol 7.500 kg Methyl p-hydroxybenzoate 0.100 kg Propyl p-hydroxybenzoate 0.025 kg Phenylephrine HC1 0.125 kg Sodium citrate 0.150 kg Disodium edetate 0.050 kg Sodium metabisulphite 0.250 kg Hamamelis water · · 25.000 kg Distilled water 15.925 kg Physical characteristics for the large scale batch were measured as follows: DENSITY (Paar DMA 38 Density Meter) Measuring the density of 2 samples at 20°C.
Results: a) 1.0143 g/cm b) 1.0144 g/cm pH Measurements (Laboratory pH meter PHM 92) Measuring the pH values in 2 samples at 20°C Results: a) 6.07 b) 6.06 Viscosity Measurements Measuring viscosity of 2 samples using a Brookfield DVII+ Viscometer (Set up in spindle S96, 10 RPM at 20°C) Results: a) 39 000 cps b) 40 000 cps Formulations according to the above Examples are packaged in tubes each with an applicator adapted for intrarectal administration. Alternatively the flow properties of the formulations allow administration to be carried out by hand. -15- COMPARATIVE EXAMPLES a) The suitability of Lubrajel (described below) as a gel forming agent was investigated in the Example below. Lubrajel has the following physical properties: Form Viscous gel Colour Clear, colourless pH 5.0 - 6.0 (typical) Flash point non-flammable Solubility in complete Lubrajel can be described as a hydrated polymeric complex, the water of hydration of which is subject to change with the humidity of the atmosphere to which it is exposed. It is a clathrate formed by the reaction of sodium glycerate with a methacrylic acid polymer, stabilized with a small amount of propylene glycol, followed by controlled hydration of the resultant product. This glycerate polyhydrate complex is remarkably stable, releasing its combined water only with difficulty.
The addition of small amounts of methyl and propyl p-hydroxybenzoates helps control microbial growth.
Lubrajel is characterised by its non-allergenic properties and its excellent moisturising qualities. It is used as a vaginal lubricant and as a lubricant in endoscopy and hence was expected to produce a satisfactory vehicle.
The suitability of Lubrajel in producing a hemorrhoidal gel formulation was examined as follows: 1. Lubrajel MS showed a viscosity of > 99 xlO3 cps @ 10 rpm/S96. When diluted with water up to 40% w/w the mixture had an acceptable texture and viscosity ( ca. 80 x 103 cps @ 10 rpm/S96). 2. To the previous gel 0.25% w/w phenylephrine HQ powder was added. ■16- Result: Viscosity ca. 26 x 103 cps @ 10 rpm/S96 The addition of a salt caused a marked decrease in viscosity indicating ionic materials apparently destroy the clathrate structure.
The viscosity value and texture for this topical formulation were unacceptable. 3. Addition of: 0.25% w/w phenylephrine HC1 0.3% w/w Na citrate 0.5% w/w Na metabisulphite 0.1% w/w disodium edetate to Lubrajel MS :.λ Result: Viscosity - 17 x 103 cps @ 10 rpm/S96 The addition of salts as powders broke the Lubrajel structure decreasing viscosity remarkably.
The viscosity value and texture for this topical formulation were unacceptable. 4. Pre-dissolved phenylephrine HC1 in water to final concentration of 50% w/w Lubrajel MS, 0.25% w/w phenylephrine HC1.
Result: Viscosity ~ 30 x 103 cps @ 10 rpm/S96 b) A Carbopol gel was formed containing phenylephrine as active. The resulting gel was found to be very watery and non-lubricating.
The excellent lubricating properties of the formulation of this invention were demonstrated by comparative test described below.
LUBRICITY STUDY A lubricity test was performed comparing lubricity of Lubrajel MS (viscosity 80,000 cps) from step 1 above with the Natrosol formulation described in Example 2 above (viscosity 66,000).
In this test 15 people were asked to apply the formulations to their fingers and report which gel had a more lubricating feel, giving a greasier sensation. Thirteen answered that the Natrosol gel of Example 2 felt more lubricating whereas only one answered in favour of the Lubrajel MS gel of step 1 and one expressed no preference.
Claims (9)
1. Use of an aqueous gel composition which contains one or more drugs effective in treating haemorrhoids and a carrier comprising a water soluble cellulose derivative as gelling agent in an amount from about 0.2% to about 10% by weight of the total composition, propylene glycol as humectant in an amount of from about 5% to about 45% by weight of the total composition and water in an amount up to about 94% by weight of the total composition in the preparation of a medicament substantially described in the specification for treating haemorrhoids and/or anorectal disorders in a human by admiiiistration intrarectally and/or to the anorectal region.
2.. A use according to Claim 1 wherein the drug is selected from one or more of the ~ following: astringents, vasoconstrictors, antiiflammatories and/or local anaesthetics.
3. A use as claimed in Claim 2 in which the drug is hydrophilic.
4. A use according to Claim 2 wherein the astringent is hamamelis water.
5. A use according to Claim 4 wherein the hamamelis water is present in an amount from about 10 to about 60% by weight of the total composition.
6. A use according to Claim 5 wherein the hamamelis water is present in an amount about 50% by weight of the total composition.
7. A use according to any one of Claims 2' to 6 in which the composition comprises a vasoconstrictor selected from phenylephrine hydrochloride, ephedrine sulphate, epinephrine and epinephrine hydrochloride and if required an antioxidant system.
8. A use according to Claim 7 wherein the composition comprises phenylephrine hydrochloride in an amount up to about 0.35 % w/w of the total composition and the ., antioxidant system comprises sodium citrate, sodium metabisulpbite and disodium edetate.
9. A use according to any one of the preceding Claims wherein the cellulose derivative is one of the following: hydroxyethylcellulose, hydroxypropylmethylcellulose, methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcelulose and carboxymethylcellulose or a combination thereof. -20- 115391/2 hydrochloride in an amount from about 0.2 to 0.3% by weight and distilled water per cent by weight. For the Applicants
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9422571A GB9422571D0 (en) | 1994-11-09 | 1994-11-09 | Haemorrihoidal compositions and method of use |
Publications (2)
Publication Number | Publication Date |
---|---|
IL115891A0 IL115891A0 (en) | 1996-01-31 |
IL115891A true IL115891A (en) | 2001-04-30 |
Family
ID=10764101
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL11589195A IL115891A (en) | 1994-11-09 | 1995-11-06 | Hemorrhoidal compositions and their use |
Country Status (31)
Country | Link |
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US (3) | US6565850B2 (en) |
EP (1) | EP0785770B1 (en) |
JP (1) | JP4555402B2 (en) |
KR (1) | KR100385247B1 (en) |
CN (1) | CN1101181C (en) |
AR (1) | AR002944A1 (en) |
AT (1) | ATE197122T1 (en) |
AU (1) | AU715566B2 (en) |
BR (1) | BR9509710A (en) |
CA (1) | CA2204769C (en) |
CZ (1) | CZ292100B6 (en) |
DE (1) | DE69519235T2 (en) |
DK (1) | DK0785770T3 (en) |
ES (1) | ES2151968T3 (en) |
FI (1) | FI119498B (en) |
GB (1) | GB9422571D0 (en) |
GR (1) | GR3034784T3 (en) |
HK (1) | HK1008187A1 (en) |
HU (1) | HU221480B (en) |
IL (1) | IL115891A (en) |
MX (1) | MX9703429A (en) |
NO (1) | NO319253B1 (en) |
NZ (1) | NZ295211A (en) |
PL (1) | PL182403B1 (en) |
PT (1) | PT785770E (en) |
RO (1) | RO116766B1 (en) |
RU (1) | RU2159119C2 (en) |
SK (1) | SK283421B6 (en) |
TW (1) | TW501932B (en) |
WO (1) | WO1996014828A1 (en) |
ZA (1) | ZA959438B (en) |
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AU2012202731B2 (en) * | 2005-06-17 | 2014-06-19 | Wisconsin Alumni Research Foundation | Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapy |
US8114914B2 (en) | 2005-06-17 | 2012-02-14 | Wisconsin Alumni Research Foundation | Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapy |
AU2014202738B2 (en) * | 2005-06-17 | 2016-05-12 | Wisconsin Alumni Research Foundation | Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapy |
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US10022339B2 (en) | 2006-04-21 | 2018-07-17 | The Procter & Gamble Company | Compositions and methods useful for treatment of respiratory illness |
US20070249727A1 (en) | 2006-04-21 | 2007-10-25 | The Proctor & Gamble Company | Compositions and kits useful for treatment of respiratory illness |
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JP5369389B2 (en) * | 2006-05-25 | 2013-12-18 | 大正製薬株式会社 | Acupuncture composition |
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CN101152166B (en) * | 2007-09-06 | 2010-12-08 | 武汉大学 | Isoliquirtigenin gelling agent for treating hemorrhoids and method of preparing the same |
PE20091084A1 (en) * | 2007-12-07 | 2009-07-23 | Schering Plough Healthcare | PHARMACEUTICAL FORMULATIONS OF PHENYLPHRINE AND COMPOSITIONS FOR TRANSMUCOSAL ABSORPTION |
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US20090297643A1 (en) * | 2008-06-02 | 2009-12-03 | Micro-Dose Life Sciences, Llc | Botanical composition and its uses |
US9545391B2 (en) * | 2010-08-11 | 2017-01-17 | Hemaway Llc | Medicated ointment for treating hemorrhoid and method of using the same |
ITMI20111732A1 (en) * | 2011-09-27 | 2013-03-28 | Bsdpharma Srl | PHARMACEUTICAL FORMULATIONS FOR THE REDUCTION OF THE CRUSED SENSITIZATION BETWEEN THE COLUMN AND THE UROGENITAL DISTRICT WITH NON-PHARMACOLOGICAL MEANS. |
JP5697573B2 (en) * | 2011-10-14 | 2015-04-08 | 大正製薬株式会社 | Gelling hemorrhoid treatment containing a cooling agent |
US8778365B1 (en) | 2013-01-31 | 2014-07-15 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9433680B2 (en) | 2013-01-31 | 2016-09-06 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
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CN103919952A (en) * | 2014-04-21 | 2014-07-16 | 张维芬 | Gel preparation for treating hemorrhoids and preparation method thereof |
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FR3108841B1 (en) * | 2020-04-06 | 2023-11-03 | Algotherapeutix | TOPICAL PHARMACEUTICAL COMPOSITION IN AQUEOUS GEL FORM COMPRISING AT LEAST AMITRIPTYLINE |
IT202000010924A1 (en) * | 2020-05-13 | 2021-11-13 | Neilos S R L | "COMPOSITION FOR THE PREVENTION AND TREATMENT OF DISEASES OF THE CIRCULATORY SYSTEM AND RELATED SYMPTOMS" |
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-
1994
- 1994-11-09 GB GB9422571A patent/GB9422571D0/en active Pending
-
1995
- 1995-04-05 US US08/417,345 patent/US6565850B2/en not_active Expired - Lifetime
- 1995-11-06 IL IL11589195A patent/IL115891A/en not_active IP Right Cessation
- 1995-11-07 ZA ZA959438A patent/ZA959438B/en unknown
- 1995-11-09 PT PT95936647T patent/PT785770E/en unknown
- 1995-11-09 CN CN95197107A patent/CN1101181C/en not_active Expired - Lifetime
- 1995-11-09 DK DK95936647T patent/DK0785770T3/en active
- 1995-11-09 KR KR1019970703098A patent/KR100385247B1/en not_active IP Right Cessation
- 1995-11-09 DE DE69519235T patent/DE69519235T2/en not_active Expired - Lifetime
- 1995-11-09 CZ CZ19971392A patent/CZ292100B6/en not_active IP Right Cessation
- 1995-11-09 AR ARP950100112A patent/AR002944A1/en not_active Application Discontinuation
- 1995-11-09 HU HU9702453A patent/HU221480B/en not_active IP Right Cessation
- 1995-11-09 PL PL95320487A patent/PL182403B1/en not_active IP Right Cessation
- 1995-11-09 NZ NZ295211A patent/NZ295211A/en not_active IP Right Cessation
- 1995-11-09 CA CA002204769A patent/CA2204769C/en not_active Expired - Fee Related
- 1995-11-09 AU AU38503/95A patent/AU715566B2/en not_active Expired
- 1995-11-09 ES ES95936647T patent/ES2151968T3/en not_active Expired - Lifetime
- 1995-11-09 BR BR9509710A patent/BR9509710A/en active IP Right Grant
- 1995-11-09 EP EP95936647A patent/EP0785770B1/en not_active Expired - Lifetime
- 1995-11-09 SK SK587-97A patent/SK283421B6/en not_active IP Right Cessation
- 1995-11-09 RU RU97109845/14A patent/RU2159119C2/en not_active IP Right Cessation
- 1995-11-09 AT AT95936647T patent/ATE197122T1/en active
- 1995-11-09 WO PCT/GB1995/002629 patent/WO1996014828A1/en active IP Right Grant
- 1995-11-09 JP JP51582696A patent/JP4555402B2/en not_active Expired - Lifetime
- 1995-11-09 RO RO97-00874A patent/RO116766B1/en unknown
-
1996
- 1996-02-27 TW TW085102281A patent/TW501932B/en not_active IP Right Cessation
-
1997
- 1997-05-07 FI FI971969A patent/FI119498B/en not_active IP Right Cessation
- 1997-05-07 NO NO19972125A patent/NO319253B1/en not_active IP Right Cessation
- 1997-05-09 MX MX9703429A patent/MX9703429A/en unknown
-
1998
- 1998-07-20 HK HK98109293A patent/HK1008187A1/en not_active IP Right Cessation
-
2000
- 2000-11-08 GR GR20000402473T patent/GR3034784T3/en unknown
-
2003
- 2003-04-08 US US10/409,359 patent/US20040037888A1/en not_active Abandoned
-
2006
- 2006-09-07 US US11/470,979 patent/US20070003627A1/en not_active Abandoned
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